Role of the RNA modifications 2’-O-methylation and N6-methyladenosine in viral pathogenicity
Research area: Molecular Immunology
Viral RNA is sensed by various pattern recognition receptors such as Toll-like receptors and RIG-I like helicases (RLH) leading to immune activation and type I interferon production. Several viral evasion strategies targeting signal transduction or modifying 5’ RNA ends have been described. However, RNA modifications such as 2’-O-methylation or N6-methyladenosine that antagonize or negatively modulate TLR7-mediated RNA recognition have not been considered. This proposal addresses the possible role of host cell-derived 2’-O-methylations in genomic influenza A virus (IAV) RNA and predicted host-specific methylation differences for altered immune response, infectivity and pathogenicity. In addition, we will analyze the effect of antagonistic 2’-O-methylated host cell tRNA, that is associated with VSV or SeV, on early immune escape from TLR7 recognition in plasmacytoid dendritic cells. Importantly, we will also investigate the currently unknown function of N6-methyladenosine (m6A) in influenza mRNA. Since the number and position of predicted m6A methylation sites in IAV mRNA strongly vary among different IAV strains, we hypothesize an influence on immune recognition, viral replication and/or pathogenicity.
Overall, this analysis will provide a more sophisticated understanding of the immune response to virus infection or pathogenicity and may lead to new approaches for antiviral drug development.
Project-related publications of the investigator:
- Jung S, von Thülen T, Laukemper V, Pigisch S, Hangel D, Wagner H, Kaufmann A, Bauer S. A single naturally occurring 2′-O-methylation converts a TLR7- and TLR8-activating RNA into a TLR8-specific ligand. PLoS One. 2015 Mar 18;10(3):e0120498. doi:10.1371/journal.pone.0120498. eCollection 2015.
- Oldenburg M, Krüger A, Ferstl R, Kaufmann A, Nees G, Sigmund A, Bathke B, Lauterbach H, Suter M, Dreher S, Koedel U, Akira S, Kawai T, Buer J, Wagner H, Bauer S, Hochrein H, Kirschning CJ. TLR13 recognizes bacterial 23S rRNA devoid of erythromycin resistance-forming modification. Science. 2012 Aug 31;337(6098):1111-5. doi: 10.1126/science.1220363. Epub 2012 Jul 19.
- Bauer, S., C. J. Kirschning, H. Hacker, V. Redecke, S. Hausmann, S. Akira, H. Wagner, and G. B. Lipford. 2001. Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc Natl Acad Sci U S A 98:9237-42.
- Hamm, S., A. Heit, M. Koffler, K. M. Huster, S. Akira, D. H. Busch, H. Wagner, and S. Bauer. 2007. Immunostimulatory RNA is a potent inducer of antigen-specific cytotoxic and humoral immune response in vivo. Int Immunol 19:297-304.
- Hamm, S., E. Latz, D. Hangel, T. Muller, P. Yu, D. Golenbock, T. Sparwasser, H. Wagner, and S. Bauer. 2010. Alternating 2′-O-ribose methylation is a universal approach for generating non-stimulatory siRNA by acting as TLR7 antagonist. Immunobiology 215:559-69.
- Heil, F., H. Hemmi, H. Hochrein, F. Ampenberger, C. Kirschning, S. Akira, G. Lipford, H. Wagner, and S. Bauer. 2004. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303:1526-9.
- Heil, F., P. Ahmad-Nejad, H. Hemmi, H. Hochrein, F. Ampenberger, T. Gellert, H. Dietrich, G. Lipford, K. Takeda, S. Akira, H. Wagner, and S. Bauer. 2003. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur J Immunol 33:2987-97.
- Jöckel, S., G. Nees, R. Sommer, Y. Zhao, D. Cherkasov, H. Hori, G. Ehm, M. Schnare, M. Nain, A. Kaufmann, and S. Bauer. 2012. The 2′-O-methylation status of a single guanosine controls transfer RNA-mediated Toll-like receptor 7 activation or inhibition. J Exp Med 209:235-41.
- Jurk, M., F. Heil, J. Vollmer, C. Schetter, A. M. Krieg, H. Wagner, G. Lipford, and S. Bauer. 2002. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 3:499.
- Rutz, M., J. Metzger, T. Gellert, P. Luppa, G. B. Lipford, H. Wagner, and S. Bauer. 2004. Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. Eur J Immunol 34:2541-50.